This invitation provides relevant background information, summarizes
EPA's interest in the topic areas, and describes the application and
review process.

Background

During fiscal year 1995 EPA increased funding for its investigator
initiated research grants program. For fiscal year 1996, EPA anticipates
a second increase, subject to the 1996 Federal appropriation process.
In December 1995 EPA issued a Request for Applications (RFA) which
summarized its interest in 9 programmatic areas. This announcement
supplements that RFA and solicits research proposals in 3 additional
topical areas. Additional programs involving cooperation with the
National Science Foundation and other agencies were announced separately.

EPA Mission and R & D Strategy

The mission of EPA - and its unique role - is the protection of both
environmental quality and human health through effective regulations
and other policy implementation. Achievement of this mission requires
the application of sound science to the assessment of environmental
problems and evaluation of possible solutions. A significant challenge
is to support both long-
term research that anticipates future environmental problems as well
as to fill significant gaps in knowledge relevant to meeting current
Agency goals. This Request for Applications and the joint solicitations
with other agencies are important steps toward ensuring that EPA can
provide a sound scientific foundation as the country enters a new
generation of environmental protection.

EPA recently reorganized its research programs to focus on the reduction
of uncertainty associated with risk assessment and reduction of risks
to human health and ecosystems. Through its laboratories and through
grants to universities and other not-for-profit institutions, EPA
will promote research in both domains, according the highest priority
to those areas where risk assessors are most in need of new concepts,
methods, and data. At the same time, EPA will foster the development
and evaluation of new risk reduction technologies across a spectrum,
from pollution prevention, through end-of-pipe controls, to remediation
and monitoring. In all areas, EPA is interested in research that recognizes
issues relating to environmental justice, the Agency's effort to achieve
equal protection from environmental and health hazards for all people
without regard to race, economic status, or culture.

Research Programs of Interest

11. Endocrine Disruptors

Reports have been accumulating that both humans and wildlife species
have experienced adverse health consequences resulting from exposure
to environmental pollutants that interact with the endocrine system.
These pollutants are collectively referred to as "endocrine disruptors,"
a term broadly defined as "an exogenous agent that interferes
with the production, release, trans
port, metabolism, binding, action, or elimination of natural hormones
in the body responsible for the maintenance of homeostasis and the
regulation of reproductive and developmental processes." The
Agency is concerned with potential effects posed by environmental
agents that act as hormones or anti-hormones, as well as chemicals
or mixtures which perturb components of the endocrine system through
as yet uncharacterized modes of action.

To date, problems have been identified primarily in domestic or wildlife
species with high exposure to organochlorine compounds, including
DDT and its metabolites, PCBs and dioxins, some organometals, unidentified
components of certain types of complex effluents and emissions, and/or
to naturally occurring plant estrogens. Whether similar effects are
occurring in the general human or wildlife population is unknown.
Several reports of declines in the quality and quantity of sperm production
in humans over the last four decades and reported increases in incidence
of certain cancers (breast, prostate, testicular) have led to speculation
about environmental etiologies. Correlational evidence suggests that
specific populations of animals such as birds, fish, reptiles, and
mammals have been, or currently are being, adversely impacted by exposure
to environmental contaminants that may manifest effects through the
endocrine system.

Refinement of methods to monitor and characterize exposure of
humans and/or wildlife to endocrine disruptors, including aspects
such as exposure half-life, speciation, uptake, and phase equilibrium.

Development and validation of models to estimate exposure to
endocrine disruptors from different sources via multiple pathways.

Development and validation of biomarkers of endocrine disruptor
exposure and effect.

Development and validation of in vitro and short-term in vivo
test systems to screen for chemicals with specific mechanisms
of action expressed via different endocrine pathways; test systems
that are applicable across multiple phylogenetic levels are of
particular interest.

Development of Physiologically-Based Pharmacokinetic (PB-PK),
Physiologically-Based Toxicokinetic (PB-TK), and Biologically-Based
Dose-Response (BBDR) models that incorporate key species-specific
parameters critical to the extrapolation of effects across phyla.

Refinement and validation of methods and models that relate
effects observed at subcellular levels to adverse impacts in individuals
(both human and wildlife species) and in wildlife populations.

Funding: Up to $3.5 million is expected to be available in
fiscal year 1996 for awards in this program area. The projected award
range is $100,000 - $200,000/year for up to 3 years.

12. Role of Interindividual Variation in Human Susceptibility
to Cancer

Background

In 1994, the National Academy of Sciences released the report, Science
and Judgment in Risk Assessment. This report, which was produced in
response to the Clean Air Act Amendments of 1990, evaluated risk assessment
methods at EPA and drew a series of conclusions and recommendations.
Included was the issue of variation in human susceptibility. On this
issue, the report concluded that EPA's consideration of interindividual
variability has been limited largely to noncarcinogenic effects, such
as asthmatic responses to sulfur dioxide exposure, and suggested that
EPA include consideration of interindividual variability in its cancer
risk assessments. The NAS recommended that:

Federal agencies should sponsor molecular, epidemiological,
and other types of research to examine the causes and extent of
interindividual variability in susceptibility to cancer and the
possible correlations between susceptibility and such covariates
as age, race, ethnicity, and sex. Results should be used to refine
estimates of risks to individuals and the general population.

EPA should increase its efforts to validate or improve the default
assumption that humans on average have the same susceptibility
as humans in epidemiological studies, the most sensitive animals
tested, or both.

The NAS report stated that human beings vary substantially in their
inherent susceptibility to carcinogenesis, both in general and in
response to any specific stimulus or mechanism. Point estimates of
carcinogenic potency of a substance will not apply to all individuals
in the population. They further stated that variability affects each
step in the carcinogenic process (e.g., carcinogenic uptake and metabolism,
DNA damage, DNA repair and misrepair, cell proliferation, tumor progression,
and metastasis) and that the variability arises from many independent
factors, some inborn and some environmental. NAS stated that it appeared
that some of the individual determinants are distributed bimodally
or perhaps trimodally in the population (e.g., hypersusceptible people
such as those with germ-line mutations in tumor suppressor genes)
while other determinants seemed to be distributed more or less continuously
and unimodally with either narrow or broad variances (e.g., the kinetics
or activities of enzymes that activate or detoxify particular pollutants).

Description

In this RFA, EPA is interested in: (1) the identification of human
genetic polymorphisms which can affect carcinogenic risk from environmental
agents, (2) the quantitative relationship of these polymorphisms to
the risk of cancer from environmental agents, and (3) the distribution
of such polymorphisms in the general population. Response to this
RFA should address human variation in susceptibility with regard to
polymorphisms and a specific chemical carcinogen of concern to the
Agency.

Funding: Up to $2.0M is expected to be available in Fiscal
Year 1996 for this program area. The projected award range is $100,000
- $200,000/year for up to 3 years.

13. Risk-Based Decisions for Contaminated Sediments

Many persistent chemical contaminants in aquatic ecosystems eventually
accumulate in sediments where they may adversely affect the benthic
biota, become a source of contamination in the water column, accumulate
in biological tissues, and enter pelagic and human food chains. Contaminated
sediments now appear to be the main source of toxic contaminants in
many bays, lakes, and rivers. For example, of the Great Lake's 42
Areas of Concern, 33 have degraded water quality problems associated
with contaminated sediments. Because of their potential adverse impacts,
the long periods of time associated with natural assimilation of many
in-place contaminants, and the high costs of mitigation, sediments
have become a focus of concern for EPA.
The following areas of research provide the framework for the competition:

Risk-Based Assessments

Hazard Identification

All assessment techniques, either biological or chemical, need validation
of their ability to predict impacts on indigenous aquatic communities.
When laboratory data and test systems are being used to predict contaminated
sediment impacts, there needs to be a strong lab-to field association.
Research is needed to validate these techniques using a risk-based
approach. Validation efforts must consider the uncertainty associated
with the assessment and the degree of protection offered to the aquatic
community.

The effects of contaminants associated with sediments is often manifested
through aquatic food chains. Research and mathematical modeling is
needed to accurately characterize the transfer of toxic substances
from their source to the sediments, from sediments to organisms, and
organism to organism.

Dose-Response

Short-term sediment toxicity test methods to examine aquatic life
effects using laboratory animals exist. In addition, there are some
theoretical models to predict whether certain single chemical concentrations
will have an adverse impact on benthic communities. Most contaminated
sediments contain mixtures of chemicals; thus, mixture toxicity research
and modeling both for organic substances and trace metals are needed
to complement single chemical assessments. Further research is needed
to expand the number and kind of species being tested.

Exposure Assessment

Knowledge of the fate and bioavailability of toxic substances in sediments
is sometimes highly speculative. Additional knowledge is needed on:
(1) the fate of toxic substances during resuspension, especially during
severe events, and biological, chemical and physical factors con
trolling resuspension of sediments, (2) the spatial (horizontal and
vertical) and temporal extent of sediment contamination, and (3) biogeochemical
partitioning between sediments, water, and biota to better predict
bioavailability of chemicals believed to have adverse impacts.

Risk Management

Sediment Treatment

Contaminated sediments requiring treatment can result from either
sediment management operations (e.g., maintenance dredging) or remediation
efforts. The environmental risks associated with these sediments need
to be reduced. For example, better methods to predict the extent to
which dredging operations resuspend and transport contaminants to
less contaminated areas are needed. Research is needed to develop
innovative treatment options for sites with large volumes of contaminated
sediment (e.g., harbors).

Proposals that address the above mentioned needs are invited. Proposals
must relate how the research will facilitate better risk assessments
and risk management decisions.

Funding: Approximately $2.0 million is expected to be available
for awards under this program area. The projected award range is $100,000
- $200,000/year for up to 3 years.

The Application

Proposed research projects must be designed to advance the state of
knowledge in the indicated areas. The Application Kit for Assistance
contains detailed instructions on how to prepare your application.
The application kit is available at most institutional offices of
sponsored research or may be obtained from EPA at:
U.S. Environmental Protection Agency
National Center for Environmental Research and Quality Assurance
(8703)
401 M Street SW
Washington DC 20460
Phone: (202) 260-3837

Fax: (202) 260-2039
Each application must contain the following:

A. Application for Federal Assistance (Standard Forms 424 and 424A).
These forms must have original signature.

B. A detailed, itemized budget for each year of the proposed project.

C. A budget justification describing the basis for calculating the
personnel, fringe benefits, travel, equipment, supplies, contractual
support, and other costs identified in the itemized budget.

D. An abstract containing the following information: The project
title, the names and affiliations of all investigators, and a summary
of the objectives, expected results, and approach described in the
proposal. The abstract must not exceed one (1) 8.5 x 11 inch page
of single-spaced standard 12 point type with 1 inch margins.

E. A Description of the Project. This description must not exceed
fifteen (15) pages. All pages must be consecutively numbered, 8.5
x 11 inch, single-spaced standard 12 point type with 1 inch margins.
The description must provide the following information (1-5):

1. Objectives: List objectives of the proposed research and/or
the hypotheses being tested during the project.

2. Expected Results or Benefits: Describe the results you expect
to achieve during the project and the benefits of success.

3. Approach: Outline the methods, approaches, and techniques that
you intend to employ in meeting the objective stated above.

4. General Project Information: Discuss other information relevant
to the potential success of the project. This might include facilities,
project schedules, proposed management, interactions with other
institutions, etc.

L. Copy of State Clearing House Approval Notification (see Application
Kit to determine if applicable).

M. In lieu of the Application Receipt Letter provided in some
Application Kits, the applicant must include a blank self-addressed,
stamped post card with the application.

The application must contain all of the above, in the order listed.

Sorting Codes

In order to facilitate proper assignment and review of applications,
applicants are asked to identify the topic area in which their application
is to be considered. Applications must be identified by printing the
appropriate Sorting Code (see below) in block 10 of the SF-424.

Endocrine Disruptors---96-NCER-11
Role of Interindividual Variation in Human Susceptibility to Cancer---96-NCER-12
Risk-Based Decisions for Contaminated Sediments---96-NCER-13

The Sorting Code must be placed in Block 10 of SF 424.

The Sorting Code must also be included in the address on the package
that is submitted to EPA (see next section on how to apply).

How to Apply

To be considered, the original and ten (10) copies of the fully developed
research grant application
and five (5) additional copies of the abstract (fifteen in all), must
be received (post-marked if sent by U.S. Mail) by the National Center
for Environmental Research and Quality Assurance no later than 4:00
P.M. EST on the closing date assigned to these topic areas, May 1,
1996.

The application and abstracts must be prepared in accordance with
instructions in the Application Kit for Federal Assistance and this
RFA. Informal, incomplete, or unsigned proposals will not be considered.
Completed applications should be sent via regular or express mail
to:U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research (8703)
Sorting Code: 96-NCER-X [X=11, 12, or 13]
Room M2426
401 M Street SW
Washington DC 20460
Applications sent via express mail should have the following telephone
number listed on the express mail label: (202) 260-3837

Quality Assurance

Data sets resulting from EPA-funded environmental research often are
used by government offi
cials when establishing standards or when making other policy decisions.
Explicit indicators of data quality are essential for determining
whether a particular data set is appropriate for use in a specific
context. To that end, EPA regulations require that grant-funded projects
address quality assurance.

The application must include a quality assurance narrative statement,
not to exceed two pages, which for each item listed below, either
presents the required information or provides justification as to
why the item does not apply to the proposed research.

The intended use of the data and the associated acceptance criteria
for data quality (i.e., precision, accuracy, representativeness,
completeness, and comparability).

Project requirements for precision, accuracy, representativeness,
completeness, and comparability, and how these will be determined.

Procedures for selection of samples or sampling sites, and collection
or preparation of samples.

Description of measurement methods or test procedures, with
a statement of performance characteristics if methods are non-standard.

Standard quality assurance/quality control procedures (e.g.,
American Society for Testing Materials, American Public Health
Association, etc.) to be followed. Non-standard procedures must
be documented.

Data reduction and reporting procedures, including description
of statistical analyses to be used.

Guidelines and Limitations

Subcontracts for research to be conducted under the grant that exceed
40% of the total direct cost of the grant for each year in which the
subcontract is awarded will be subject to special review.

Additional Requirements

Researchers will be expected to participate in an annual All Investigator's
Meeting with EPA researchers and other grantees and cooperators to
report on research activities and to discuss issues of mutual interest.

Eligibility

Academic and not-for-profit institutions located in the U.S., and
state or local governments are eligible under all existing authorizations.
Profit making firms are eligible only under certain laws, and then
under restrictive conditions, including the absence of any profit
from the project. Federal agencies and federal employees are not eligible
to participate in this program. Potential applicants who are uncertain
of their eligibility should contact EPA's Grants Operations Branch
at (202) 260-9266.

Review and Selection

All grant applications are initially reviewed by EPA to determine
their legal and administrative acceptability and responsiveness to
this solicitation. Acceptable applications are then reviewed by an
appropriate technical peer review group. This review is designed to
evaluate and rank each proposal according to its scientific merit.
Each review group is composed primarily of non-EPA scientists, engineers,
social scientists, and/or economists who are experts in their respective
disci
plines. All reviewers are proficient in the technical areas that they
are reviewing. The reviewers use the following criteria in their reviews:

quality of the research plan (including theoretical and/or experimental
design, originality, and creativity);

qualifications of the principal investigator and staff, including
knowledge of relevant subject areas;

potential contribution of the research to advancing scientific
knowledge in the environmental area;

availability and adequacy of facilities and equipment; and

budget justification -- justification for equipment will receive
special attention;

responsiveness to solicitation objectives.

Funding decisions are the sole responsibility of EPA. Grants are selected
on the basis of technical merit, relevancy to the research priorities
outlined, program balance, and budget.

EPA anticipates making awards from this RFA by September 1996.

Proprietary Information

By submitting an application in response to this solicitation, the
applicant grants EPA permission to share the application with technical
reviewers both withitside of the Agency. Applications containing proprietary
or other types of confidential information will be immediately returned
to the applicant without review.

Funding Mechanism

The funding mechanism for all awards issued under this solicitation
will consist of a grant between EPA and the recipient. In accordance
with Public Law 95-224, a grant is used to accomplish a public purpose
of support or stimulation authorized by Federal statute rather than
acquisition for the direct benefit of the Agency. In using a grant
instrument, EPA anticipates that there will be no substantial involvement
during the course of the grant between the recipient and the Agency.

Contacts

Additional general information on the grants program may be obtained
by contacting:U.S. Environmental Protection Agency
National Center for Environmental Research and Quality Assurance
(8703)
401 M Street SW
Washington DC 20460
Phone: (202) 260-3837